Summary of clinical pearls

1

Chapter 1 : Fundamentals of neuropathology: introduction to neuropathology and molecular diagnostics

• a.

  Classification of glioblastoma

  • i.

    Microvascular proliferation and pseudopalisading necrosis are pathologic hallmarks of glioblastoma (GBM) and, when present, establish the diagnosis of GBM.

  • ii.

    IDH1/2 gene mutation is rare in GBM; EGFR amplification and MGMT promoter methylation are observed in approximately 40% of GBMs.

• b.

  Classification of low-grade oligodendroglioma

  • i.

    When molecular profiling of a brain tumor reveals the presence of 1p/19q co-deletion and IDH1/2 mutation, a diagnosis of oligodendroglioma is made.

  • ii.

    Histologically, oligodendrogliomas are characterized by the presence of round nuclei and perinuclear halo that has a “fried egg” appearance.

  • iii.

    Grading of oligodendrogliomas is restricted to grade II and III tumors; there is no grade I or IV oligodendroglioma; oligodendrogliomas with necrosis and microvascular proliferation are grade III.

• c.

  Classification of low-grade astrocytoma

  • i.

    Grade I gliomas are generally well circumscribed, whereas grades II–IV are diffusely infiltrating.

  • ii.

    Low-grade diffusely infiltrating gliomas that lack co-deletion of chromosomes 1p and 19q are molecularly defined as astrocytomas.

  • iii.

    While IDH1/2 gene mutation is common in low-grade diffuse astrocytomas, this is not a molecularly defining event and IDH wild-type low-grade diffuse astrocytomas also occur.

  • iv.

    Low-grade gliomas (LGGs) can progress to higher-grade neoplasms and, when they recur as GBM, are considered “secondary” GBMs.

• d.

  Classification of anaplastic astrocytoma

  • i.

    The presence of mitoses (a marker of cell division) in a diffuse glioma warrants upgrading to an anaplastic glioma (grade III).

  • ii.

    The presence of chromosome 10q loss combined with polysomy of chromosome 7 favors a molecular diagnosis of a higher-grade glioma.

• e.

  Classification of meningioma

  • i.

    Meningiomas are the most common primary brain tumor and appear as dural-based lesions often with an area of adjacent thickened dura, termed a dural “tail.”

  • ii.

    Up to 95% of meningiomas are benign WHO grade I lesions, but rarely grade II and grade III tumors can present and require additional treatment.

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Chapter 2 : Surgical considerations for brain and spine tumors

• a.

  Surgical management of posterior fossa lesions and increased intracranial pressure

  • i.

    Clinicians must be aware of symptoms of increased intracranial pressure (ICP) including early morning headache, unexplained nausea, vision changes, bilateral cranial nerve VI palsies, and papilledema.

  • ii.

    Obstructive hydrocephalus from a posterior fossa mass requires urgent or emergent surgical evaluation for resection or ventricular decompression.

  • iii.

    Children with posterior fossa pilocytic astrocytomas generally have excellent outcomes, particularly when gross total resection (GTR) is achieved.

• b.

  Surgical management of resectable brain lesions

  • i.

    Gross or near GTR with >90% of tumor resected is consistently associated with improved outcomes in uncontrolled studies of glioma.

  • ii.

    In general, surgery plays three roles in the management of glioma patients including: (1) tissue diagnosis, (2) cytoreduction of tumor, and (3) symptom relief from cerebral edema.

• c.

  Surgical management of unresectable brain lesions

  • i.

    Tumors in deep locations, adjacent to eloquent structures, or crossing the midline may not be amenable to open resection.

  • ii.

    In selected cases, laser interstitial thermal therapy (LITT) is a surgical option for tissue ablation and can be performed at the time of tissue biopsy.

• d.

  Surgical management of spinal cord lesions

  • i.

    GTR is consistently associated with improved outcomes for patients with ependymoma and should be pursued aggressively.

  • ii.

    Extramedullary tumors such as metastases, meningiomas, and schwannomas carry a different surgical risk from intramedullary lesions such as astrocytomas or ependymomas.

• e.

  Surgical management of brain metastasis

  • i.

    When evaluating a patient with a known cancer diagnosis and multiple brain lesions, surgery may be beneficial when there is a single, large (>3 cm) lesion with symptomatic cerebral edema.

• f.

  Surgical management of meningioma

  • i.

    For meningiomas that cannot be observed, surgical resection should be considered, particularly when there is brain infiltration, mass effect, or clinical symptoms.

  • ii.

    Extent of surgical resection for WHO grade 1 meningiomas is guided by the Simpson grade scale where greater extent of resection predicts lower rates of tumor recurrence.

• g.

  Surgical management of epidural spinal cord compression

  • i.

    Management of patients with osseous metastasis to the spinal cord should include assessment of new neurological symptoms, degree of spinal cord compression on axial T2-weighted MRI images at the point of greatest compression, and treatment responsiveness of the tumor type.

  • ii.

    Spinal cord decompression improves neurological outcomes for patients with new deficits including paralysis, bowel or bladder dysfunction, or sensory loss that have been present for no more than 48 hours from onset.

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Chapter 3 : Introduction to radiation therapy

• a.

  Radiation therapy for high-grade glioma (HGG)

  • i.

    The standard of care for HGG is maximal safe resection followed by combined modality therapy consisting of adjuvant radiation therapy and temozolomide. The typical radiation regimen is 60 Gy in 30 fractions (2 Gy per fraction) delivered over 6 weeks.

  • ii.

    Among the elderly or those with poor performance status, hypofractionated radiation therapy (for example, 40.05 Gy in 15 fractions delivered over 3 weeks) with temozolomide, radiation therapy alone, or temozolomide alone may be appropriate in certain patients. This decision is often guided by MGMT methylation status.

  • iii.

    External beam radiotherapy for HGG may be planned and delivered with 3D-conformal radiotherapy, intensity-modulated radiotherapy, or volumetric-modulated arc radiotherapy.

  • iv.

    Imaging follow-up should occur 1 month after completion of radiation therapy to establish a new baseline prior to continuation of additional adjuvant chemotherapy. The possibility of pseudoprogression instead of early disease progression should be considered, particularly in patients treated with concurrent temozolomide.

• b.

  Stereotactic radiosurgery (SRS) for brain metastasis

  • i.

    Among patients with a limited number of brain metastases and good prognosis, SRS is preferred over whole brain radiation therapy (WBRT). SRS achieves high rates of local control and is associated with improved cognitive function and quality of life compared to WBRT.

  • ii.

    Because of the risk of developing new brain metastases after SRS, patients should have routine surveillance imaging every 2–3 months following treatment and with longer intervals with longer time of central nervous system disease stability.

  • iii.

    Radiation necrosis is a late toxicity of SRS that develops months to years after treatment and is most commonly asymptomatic but can have associated symptoms ranging from focal neurologic deficits to generalized cognitive symptoms depending upon the location. Steroids, bevacizumab, or surgical resection are used to treat symptomatic radiation necrosis.

  • iv.

    The risk of radiation necrosis is associated with brain metastasis size and radiation dose. Fractionated radiation therapy should be considered for high-risk lesions. Alternatively, SRS can be delivered with a reduced dose or in few fractions (between two and five) to reduce risk of toxicity.

• c.

  Whole Brain Radiation Therapy (WBRT) for Brain Metastasis

  • i.

    WBRT is generally recommended for patients with diffuse brain metastases and reduces the risk of new brain metastases compared to management by SRS.

  • ii.

    WBRT improves survival for only limited sets of patients. Patients who are elderly, debilitated, or with a very poor prognosis may not benefit from WBRT in terms of survival or quality of life. Best supportive care is a reasonable alternative for these groups of patients.

  • iii.

    WBRT is most commonly delivered as 30 Gy in 10 fractions over 2 weeks.

  • iv.

    WBRT harbors significant risk of toxicity, the most severe of which is irreversible cognitive decline that may occur months to years after treatment.

  • v.

    Delivery of WBRT with intensity-modulated radiotherapy and/or volumetric-modulated arc radiotherapy allows dose adjustment to specific intracranial structures, including dose reduction to the hippocampus. This approach is termed hippocampal avoidance whole brain radiation therapy (HA-WBRT) and may reduce cognitive decline following treatment.

• d.

  Radiation therapy for spinal cord tumors

  • i.

    Radiation therapy for intramedullary spinal cord tumors is standard after surgery or at the time of progressive disease.

  • ii.

    Patients are most commonly treated with a dose between 45 to 54 Gy in 1.8 Gy daily fractions over the course of 5–6 weeks.

  • iii.

    Chronic progressive myelopathy is the most serious complication of spinal cord irradiation. It results in permanent and often progressive neurologic deficits, ranging from minor sensory and motor deficits to complete paraplegia in severe cases. There are no proven effective treatments.

  • iv.

    Proton therapy for intramedullary spinal cord tumors may be considered in some clinical scenarios, particularly for children who are at highest risk of long-term treatment-associated toxicity.

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Chapter 4 : Evidence-based approaches to chemotherapy for gliomas

• a.

  General principles of chemotherapy for gliomas

  • i.

    In general, chemotherapy has been use as a neoadjuvant, adjuvant, or concurrent treatment defined as: neoadjuvant chemotherapy is administered prior to the main or definitive treatment which is usually surgery (i.e., before surgery); adjuvant chemotherapy is administered after the main or definitive treatment; concurrent chemotherapy may be administered simultaneously with radiation therapy.

  • ii.

    Temozolomide (TMZ) is used commonly in many central nervous system (CNS) regimens due to its many favorable characteristics including good oral bioavailability, limited binding protein, and good CNS penetration with measurable levels being achieved in the cerebrospinal fluid (CSF) and in brain parenchyma following oral administration.

  • iii.

    The most frequent side effects of TMZ are nausea/vomiting and fatigue. However, approximately 20% of patients discontinue TMZ due to myelosuppression, in particular for thrombocytopenia (<100,000/mm ³ ).

  • iv.

    Procarbazine (PC), lomustine (CCNU), and vincristine (PCV) is a combined therapy used frequently to treat patients with oligodendrogliomas including both low-grade and anaplastic.

• b.

  Chemotherapy for co-deleted anaplastic oligodendrogliomas

  • i.

    IDH mutant, 1p19q co-deleted oligodendrogliomas are among the most chemosensitivity gliomas with several clinical trials having demonstrated prolonged median survival of more than 10 years by adding PCV chemotherapy to radiotherapy (RT).

  • ii.

    Clinicians should be aware of the risk of a tyramine reaction in patients taking procarbazine (included in the PCV chemotherapy regimen). This catecholamine-like reaction can occur in patients who ingest or consume tyramine-containing foods or pharmacologic agents while taking procarbazine.

• c.

  Chemotherapy for non–co-deleted anaplastic gliomas

  • i.

    The standard of care for 1p/19q non–co-deleted anaplastic gliomas includes maximal safe resection, RT, and TMZ-based chemotherapy.

  • ii.

    To date, data show that a trend toward a benefit of concomitant chemoradiation is observed in IDH mutated tumors, but not in IDH wild-type tumors.

• d.

  Chemotherapy for low-grade gliomas

  • i.

    LGGs are a heterogeneous group of tumors that include pure oligodendrogliomas, IDH mutant astrocytomas, and IDH wild-type astrocytomas.

  • ii.

    Selected LGGs are chemosensitive to alkylating therapy with recent clinical trials showing favorable outcomes in patients with 1p19q co-deleted oligodendrogliomas and frequently for IDH mutant astrocytomas, compared to IDH wild-type LGGs, which have largely not been responsive to chemotherapy.

• e.

  Chemotherapy for glioblastoma

  • i.

    Standard of care for patients with GBM includes concurrent chemotherapy followed by six cycles of adjuvant temozolomide chemotherapy and tumor treating field therapy.

  • ii.

    Methylation of the MGMT gene promoter is both prognostic of improved survival as well as predictive of a more favorable response to chemotherapy.

• f.

  Chemotherapy for recurrent gliomas

  • i.

    Treatment options for patients with recurrent gliomas are limited and generally include temozolomide, nitrosoureas, and bevacizumab.

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Chapter 5 : Evaluation of a dural-based lesion

• a.

  Clinical pearls for evaluating dural-based lesions

  • i.

    Most are T1 iso-hypointense on MRI. If they are T1 hyperintense, consider etiologies that contain methemoglobin (subacute hemorrhage), high protein, fat, melanin, or calcium.

  • ii.

    Some dural-based lesions are T2 hyperintense due to high water content. Others are T2 hypointense due to their high cellularity (particularly if the tumor cells have a high nuclear-to-cytoplasmic ratio, such as lymphoma). Some meningiomas can be fibrous and these have lower T2 signal.

  • iii.

    Diffusion restriction in dural-based lesions is variable. Diffusion restriction is an evaluation of how freely water molecules can move in a given medium. If restricted diffusion is present, then consider highly cellular tumors, such as lymphoma, cellular meningiomas, or metastases.

  • iv.

    Enhancement is a product of disruption of the blood-brain barrier. Extraaxial lesions do not have a blood-brain barrier and most avidly enhance. Meningiomas, the most common dural-based neoplasm, typically diffusely and homogeneously enhance. They often have adjacent dural enhancement/thickening that is referred to as a “dural tail.” Most other dural-based neoplasms also avidly enhance, so the presence of enhancement does not exclude more aggressive neoplasms. If the enhancement pattern is heterogenous, a low-grade meningioma is less likely.

  • v.

    Evaluate the relationship of the dural-based lesion with the brain. To establish the lesion is truly extraaxial, look for CSF between the margins of the tumor and the adjacent brain parenchyma (also called a CSF cleft). If there is an indistinct interface between the dural-based mass and the brain or if there is a large amount of edema in the brain, there is a higher likelihood that the mass will be a higher meningioma grade or a more aggressive neoplasm.

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Chapter 6 : Evaluation of a supratentorial parenchymal lesion

• a.

  Imaging features of supratentorial GBM

  • i.

    The imaging differential for a single ring-enhancing supratentorial lesion includes HGG, solitary brain metastasis, cerebral abscess, tumefactive demyelination, and subacute stroke.

  • ii.

    For such a lesion, surgical consultation and evaluation is required to establish a tissue diagnosis and guide treatment decisions.

• b.

  Imaging features of supratentorial low-grade glioma

  • i.

    The differential diagnosis of a non-enhancing supratentorial lesion on MRI includes LGG and subacute ischemia, cerebritis, an arteriovenous malformation, or herpes encephalitis

• c.

  Imaging features of CNS lymphoma

  • i.

    The imaging differential diagnosis for an enhancing lesion consistent with CNS lymphoma includes CNS lymphoma, GBM, infections (i.e., abscess, toxoplasmosis), progressive multifocal leukoencephalopathy (PML), demyelinating disorders, or metastases.

  • ii.

    Compared to malignant glioma, treatment response is considerable higher for patients with CNS lymphoma even without cytoreduction. Thus, stereotactic biopsy is favored.

• d.

  Imaging features of brain metastasis

  • i.

    The imaging differential for multifocal brain metastasis includes multifocal GBM, abscess, demyelinating disease, or CNS lymphoma (in immunocompromised patients).

  • ii.

    Multidisciplinary evaluation including radiology, neurosurgery, radiation oncology, medical oncology, and neuro-oncology help determine an optimal treatment plan.

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Chapter 7 : Evaluation of an infratentorial lesion

• a.

  General tips for imaging of the posterior fossa

  • i.

    MRI offers higher soft-tissue resolution with more qualitative data on posterior fossa lesions, though it is not available at all centers, requires a degree of technical expertise, is slower, may necessitate sedation for younger and unstable patients, and is more expensive than CT.

  • ii.

    CT is fast, less expensive, and more widely available than MRI, and offers insights into calcifications and boney involvement of lesions though with limited resolution and narrow lesion characteristics. Additionally, CT can be used to rapidly assess potentially life-threatening complications of posterior fossa masses, including hydrocephalus, acute hemorrhage, or pending herniation.

  • iii.

    In pediatric patients with space-occupying posterior fossa lesions, a primary brain tumor is by far the most likely diagnosis, with metastatic lesions in this population being exceedingly rare.

  • iv.

    In older adults, a space-occupying lesion in the posterior fossa is more likely to be a metastatic tumor or acute hemorrhage, and should prompt a comprehensive history and physical examination and consideration of additional body imaging to evaluate for a primary tumor or risk factors for stroke.

  • v.

    Location and characteristics of pediatric tumors can guide the clinician regarding a most likely diagnosis, which may include LGG, HGG, medulloblastoma, ependymoma, atypical teratoid/rhabdoid tumor, or others.

• b.

  Differential diagnosis of a midline fourth ventricular lesion

  • i.

    The imaging differential of a midline posterior fossa lesion in a child should include medulloblastoma (e.g., “M” for midline) and ependymoma. Pilocytic astrocytomas tend to occur in the lateral cerebellum.

• c.

  Differential diagnosis of a lateral cerebellar lesion

  • i.

    Lateral cerebellar cystic lesion with a mural nodule should raise suspicion for a pilocytic astrocytoma in children and for a cerebellar hemangioblastoma in adults.

• d.

  Differential diagnosis of a non-enhancing pontine lesion

  • i.

    The imaging differential diagnosis for an intrinsic pontine brainstem glioma should include causes of rhombencephalitis (e.g., infectious, inflammatory, paraneoplastic) including Listeria infection, enterovirus, other viral encephalitis (e.g., herpes simplex virus, Epstein-Barr virus [EBV], human herpesvirus 6), Behcet disease, Erdheim-Chester disease, or other etiologies.

  • ii.

    Pontine gliomas are typically expansile with enlargement of the central pons, often with the basilar artery displaced anteriorly or with the tumor appearing to engulf the artery.

• e.

  Differential diagnosis of an enhancing cerebellar lesion

  • i.

    The cerebellum is the second most common parenchymal location for brain metastasis.

  • ii.

    Management of cerebellar metastasis should include definitive tumor treatment as well as a consideration for reducing brainstem compression, maintaining CSF flow, and providing a tissue diagnosis when there is no contributory systemic malignancy present.

• f.

  Differential diagnosis of a non-enhancing cerebellar lesion

  • i.

    Acute cerebellitis is a heterogeneous clinical syndrome characterized by cerebellar ataxia or dysfunction that is attributable to a recent or concurrent infection, a recent vaccination, or an ingestion of medication.

  • ii.

    MRI imaging of typical acute bilateral cerebellitis includes metabolic diseases, demyelinative disorders, and meningitis.

  • iii.

    In cases of hemicerebellitis when imaging findings are asymmetric, the imaging differential includes dysplastic cerebellar gangliocytoma (Lhermitte-Duclos), vasculitis, and inflammatory processes related to cytarabine or other toxicities.

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Chapter 8 : Imaging of spinal lesions

• a.

  Imaging findings of spinal cord astrocytoma

  • i.

    Intramedullary spinal cord tumors account for ∼10% of primary spinal cord tumors and are most often ependymomas, which are slightly favored over astrocytomas.

  • ii.

    Most intramedullary WHO grade 1 pilocytic astrocytomas enhance on neuroimaging and may be confused with higher-grade lesions without a tissue diagnosis.

• b.

  Imaging findings of spinal cord ependymoma

  • i.

    Enhancing spinal cord tumors can mimic inflammatory and infectious lesions in the spinal cord including transverse myelitis, multiple sclerosis, neuromyelitis optic spectrum disorder, infectious myelitis, and other related conditions.

• c.

  Imaging findings of spinal cord hemangioblastoma

  • i.

    Spinal hemangioblastomas are the prototypical tumor associated with von Hippel Lindau (vHL) disease.

  • ii.

    Hemangioblastomas associated with vHL have earlier onset of disease, and are often solitary but can be multiple, including the cerebellum.

• d.

  Imaging findings of peripheral nerve sheath tumors

  • i.

    Schwannomas and neurofibromas account for up to one-third of intradural spinal cord tumors and appear as homogeneously enhancing extramedullary masses.

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Chapter 9 : Evaluation of peripheral nerve lesions

• a.

  Imaging findings of a solitary neurofibroma

  • i.

    The vast majority of neurofibromas are sporadic and not associated with neurofibromatosis type 1 (NF1).

  • ii.

    Characteristic MRI features include heterogeneous enhancement on T1-weighted post-contrast and hyperintensity on T2-weighted and short tau inversion recovery (STIR) sequences. A target and/or split-fat sign may be seen.

  • iii.

    The main differential diagnosis for a neurofibroma is schwannoma, and these two entities may be difficult to distinguish based on MRI alone.

• b.

  Imaging findings of plexiform neurofibromas in NF1

  • i.

    Plexiform neurofibromas (pNFs) affect up to 60% of patients with NF1.

  • ii.

    Although histologically benign and typically slow growing, pNFs can cause significant morbidity due to local mass effect and infiltration of vital anatomic structures. A small proportion of pNFs can transform into malignant peripheral nerve sheath tumors.

  • iii.

    A regional MRI with contrast-enhanced and STIR sequences of the affected region should be obtained. Whole-body MRI may be useful to assess a patient’s baseline tumor burden.

• c.

  Imaging findings of malignant peripheral nerve sheath tumors (MPNSTs)

  • i.

    Rapid development or changes of symptoms (e.g., tumor growth, pain, or neurologic dysfunction) in a patient with NF1 should prompt evaluation for MPNST.

  • ii.

    Initial workup should include a contrast-enhanced regional MRI of the affected body region. Diffusion-weighted imaging with apparent diffusion coefficient (ADC) mapping may aid in the detection of malignant foci. If the history or MRI is suggestive of malignancy, an ¹⁸ F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT should be obtained to identify metabolically active areas suitable for biopsy and histologic confirmation of malignancy.

  • iii.

    Patients should be referred to a surgeon for an image-guided biopsy and managed by an experienced multidisciplinary team including a surgeon, radiation oncologist, and medical oncologist.

  • iv.

    Prognosis is poor even with treatment, particularly for patients with advanced or metastatic disease.

• d.

  Diffuse lumbosacral nerve root thickening

  • i.

    The etiology of nerve root thickening and enhancement on spine MRI includes inflammatory/autoimmune, hereditary, infectious, and neoplastic causes.

  • ii.

    The degree of thickening, presence of significant nodularity, and degree of enhancement, and clinical and family history can help narrow down the differential diagnosis.

  • iii.

    Additional studies should be patient-specific and may include brain MRI, systemic body imaging, electromyography/nerve conduction studies, and CSF analysis.

• e.

  Non-vestibular schwannomas in NF2

  • i.

    Most schwannomas are solitary and occur sporadically. The presence of multiple schwannomas should prompt evaluation for an underlying genetic syndrome such as NF2 or schwannomatosis (SWN).

  • ii.

    A contrast-enhanced MRI of the entire brain and with thin cuts through the internal auditory canals to evaluate for vestibular schwannomas should be obtained. Similarly, a spine MRI with and without contrast is required to assess for the presence of spinal schwannomas, ependymomas, and meningiomas.

  • iii.

    Non-vestibular schwannomas may be difficult to distinguish from neurofibromas on MRI but the patient’s history and examination can help establish the diagnosis.

• f.

  Schwannomas in schwannomatosis

  • i.

    Schwannomas in SWN patients most commonly involve the spinal and peripheral nerves.

  • ii.

    Evaluation of a patient presenting with possible NF2 or SWN should include a brain MRI with thin cuts through the internal auditory canal to exclude the presence of bilateral vestibular schwannomas as well as a spine MRI.

  • iii.

    Benign schwannomas can display FDG avidity on PET/CT and mimic malignancy.

  • iv.

    Genetic testing for mutations in the NF2 , SMARCB1 , and LZTR1 genes is recommended given the significant phenotypic overlap between NF2 and SWN.

  • v.

    Management should focus on pharmacologic and non-pharmacologic treatment of pain, and if medically refractory, surgical resection of symptomatic or compressive tumors.

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